1. Field of the Invention
Retinol (vitamin A) and retinoic acid (vitamin A acid), its isomers, and certain of its analogs are known to have beneficial effects in the treatment of acne and keratinizing skin disorders.
Acne affects large patient populations and is a common inflammatory skin disorder which usually localizes on the face. Fortunately, the disease usually disappears and in the interval of months or years between onset and resolution, therapy, although not curative, can satisfactorily suppress the disease in the majority of patients.
A small number of acne patients with severe disease show little or no response to intensive therapeutic efforts including the use of high doses of oral tetracycline, dapsone, prednisone, and, in women, estrogen. In many cases, these drugs afford only a modest degree of control while the side effects of these agents severely restrict their usefulness. Patients with nodulocystic acne suffer from large, inflammatory, suppurative nodules appearing on the face, and frequently the back and chest. In addition to their appearance, the lesions are tender and often purulently exudative and hemorrhagic. Disfiguring scars are frequently inevitable.
Therapies for acne involve local and systemic administration of vitamin compounds, collectively know as retinoids. Topical application of all-trans-retinoic acid has been tried with some success, particularly against comedones or blackheads, but this condition frequently returns when the treatment is withdrawn. (All-trans-retinoic acid is also known as tretinoin. These terms are used interchangeably throughout this specification.) Additionally, retinoic acid applied topically can be highly irritating and its use can be painful for the patient depending on the concentration used and the frequency of application.
A number of side effects complicates the administration of large doses of vitamin A. Among the many symptoms of hypervitaminosis A are weight loss, desquamation of the skin, hair loss, irritation of the oral and pharyngeal mucosa, and nose bleeds, headaches, bone pain, liver toxicity due to storage of vitamin A in the liver, papilledena, pseudotumor cerebri, demineralization, and periosteal thickening of the bones. Because of these and other side effects of oral treatment with vitamin A and all-trans-retinoic acid, which produces similar side effects, they are rarely recommended for dermatopathic conditions.
The present invention relates to 13-trans-retinoic acid esters which are effective in the treatment of acne and other skin disorders when administered either topically or orally and which show few if any side effects.
2. Description of the Prior Art
The "Handbook of Nonprescription Drugs," 5th ed., 1977, A.P.A. pub., pp. 140, 319, 320, discloses the use of vitamin A and retinoic acid in the treatment of acne (unspecified). However, the disclosure of this publication is opposite to that of the subject invention, in that it states, "The systemic use of vitamin A for the treatment of acne, . . . is not warranted by clinical evidence" at p. 140; and that, "Treatments that have been abandoned or have not been proved effective include oral vitamin A" at p. 320.
J.V. Straumford reported a systemic usage of large oral doses of retinol, the alcohol form of vitamin A, over a long period of time for the treatment of acne. (Straumford, J. V., "Vitamin A: Its Effect on Acne," Northwest Med., 42: 219-255, August, 1943.) These results, however, have been disputed and systemic therapy of acne utilizing retinol has been challenged by other investigators. (Anderson, J. A. D., et al., "Vitamin A in Acne Vulgaris," Brit. Med. J., 2: 294-296, August, 1963; Lynch, F. W., et al., "Acne Vulgaris Treated with Vitamin A," Arch. Derm. 55: 355, 357, March, 1947; and Mitchell, G. H., et al., "Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A,"Arch. Derm. 64: 428-434. October, 1951.)
Topical administration of retinoic acid for the treatment of acne was reported by Kligman, et al., (Arch. Derm. 99: 469-476, 1969, U.S. Pat. No. 3,729,568). The effectivenesss of this treatment as disclosed by Kligman is often associated with a noticeable irritating effect of topically applied retinoic acid.
Esters and amides of trans-retinoic acid which are useful for the treatment of acne are claimed in U.S. Pat. Nos. 4,055,659 (all-trans-retinoyloxyacetamide), 4,126,697 (4-(all-trans-retinoyloxyacetyl)-catechol), 4,126,698 (2-hydroxyethyl all-trans-retinoate), and 4,304,787 (benzyl all-trans-retinoate). All four of these patents to Gander, et al. also disclose mixed 2-hydroxy-1-propyl and 1-hydroxy-2-propyl all-trans-retinoates, N-(3,4-methylenedioxyphenylmethyl) all-trans-retinamide, and 4-nitrobenzyl all-trans-retinoate. The effectiveness of all these compounds was shown through testing which measured increase in DNA synthesis in epidermal cells. This ability has been associated with the effectiveness of retinoic acid in the treatment of acne. See, for example, Christophers and Braun-Falco, "Stimulation of Epidermal DNA-Synthesis with Vitamin A-Acid," Arch. Klin. Exp. Derm. 232: 427-433 (1968) and Wolfe, et al., "Changes in Epidermal Differentiation After Vitamin A Acid," Arch. Klin. Exp. Derm. 237: 744-795 (1970). No claim is made and no testing is disclosed in the Gander, et al. patents which indicates that the esters or amides show fewer or greater side effects than trans-retinoic acid.
The process for treating acne vulgaris topically utilizing retinal, the aldehyde form of vitamin A, is disclosed in U.S. Pat. No. 3,932,665. The aldehyde form, unlike the acid form of vitamin A, exerts its therapeutic effect without producing irritation, inflammation, erythema, or peeling of the skin. This patent also discloses the topical use of 13-cis-retinal in the treatment of acne vulgaris.
The method of treating acne with C-20 and C-22 vinylogs of desmethyl retinoic acid is disclosed in U.S. Pat. No. 3,882,244. These vinylogs as disclosed in the patent are applied topically to the site of the acne infection as a solution, ointment, or powder. The treatment of acne vulgaris with retinoic acid analogs particularly 11-(2',6',6'-trimethylcyclohex-1'-enyl-1')-5,9-dimethylundeca-2,4,6,8,10-p entenoic acid is disclosed in U.S. Pat. No. 3,934,028. This compound can be used either internally or topically. When taken orally, the daily dosage of this compound ranged from 30-300 mg taken over from 2 to 8 weeks. However, there is no indication that the compound leads to remission from the disease after administration of the compound is withdrawn.
Other drugs presently used in the treatment of acne include benzoyl peroxide, tretinoin (all-trans-retinoic acid, Retin-A-Ortho), clindamycin, tetracyline, erythromycin, minocycline, and estrogens (for females).
Benzoyl peroxide is considered safe and effective in mild and moderate acne treatment. Tretinoin is effective but has the previously mentioned deleterious side effects, as well as accelerating photocarcinogenesis. The antiboitics are reasonably effective but have side effects such as gastrointestinal problems including reports of pseudomembranous colitis. Estrogens are sometimes effective in treating acne, but the side effects of these drugs make them less than desirable.
The use of 13-cis-retinoic acid derivatives for the treatment of acne and other skin diseases is disclosed in U.S. Pat. No. 4,677,120 of Parish et al. The derivatives are claimed for use in either oral or topical treatment of the disease. These derivatives have been found to minimize the toxic side-effects associated with the use of 13-cis-retinoic acid in the treatment of acne.
A prodrug that would retain the effectiveness of retinoic acid and would be essentially free of the deleterious side effects of retinoic acid would provide a much needed solution to a widespread problem.